title: Role of cytokines in thymus- versus peripherally derived-regulatory T cell differentiation and function.
abstract: CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are essential players in the control of immune responses. Recently, accordingly to their origin, two main subsets of Tregs have been described: thymus-derived Tregs (tTregs) and peripherally derived Tregs (pTregs). Numerous signaling pathways including the IL-2/STAT5 or the TGF-β/Smad3 pathways play a crucial role in segregating the two lineages. Here, we review some of the information existing on the distinct requirements of IL-2, TGF-β, and TNF-α three major cytokines involved in tTreg and pTreg generation, homeostasis and function. Today it is clear that signaling via the IL-2Rβ chain (CD122) common to IL-2 and IL-15 is required for proper differentiation of tTregs and for tTreg and pTreg survival in the periphery. This notion has led to the development of promising therapeutic strategies based on low-dose IL-2 administration to boost the patients' own Treg compartment and dampen autoimmunity and inflammation. Also, solid evidence points to TGF-β as the master regulator of pTreg differentiation and homeostasis. However, therapeutic administration of TGF-β is difficult to implement due to toxicity and safety issues. Knowledge on the role of TNF-α on the biology of Tregs is fragmentary and inconsistent between mice and humans. Moreover, emerging results from the clinical use of TNF-α inhibitors indicate that part of their anti-inflammatory effect may be dependent on their action on Tregs. Given the profusion of clinical trials testing cytokine administration or blocking to modulate inflammatory diseases, a better knowledge of the effects of cytokines on tTregs and pTregs biology is necessary to improve the efficiency of these immunotherapies.
authors.affiliation: Université Pierre et Marie Curie Univ Paris 06, INSERM U959 , Paris , France ; Centre National de la Recherche Scientifique, UMR 7211 , Paris , France ; Institut National de la Santé et de la Recherche Médicale (INSERM), U959, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France.
authors.forename: Jérémie David
authors.initials: JD
authors.lastname: Goldstein
authors.forename: Louis
authors.initials: L
authors.lastname: Pérol
authors.forename: Bruno
authors.initials: B
authors.lastname: Zaragoza
authors.forename: Audrey
authors.initials: A
authors.lastname: Baeyens
authors.forename: Gilles
authors.initials: G
authors.lastname: Marodon
authors.forename: Eliane
authors.initials: E
authors.lastname: Piaggio
keywords: Foxp3; IL-2; TGF-β; TNF-α; pTreg; regulatory T cells; tTreg